U.S. Pat. No. 6,017,926 (issued Jan. 25, 2000) discloses compounds of the structural formula: 
which include the two enantiomeric forms at the C-3 position (marked with an *) of the right-hand propionic acid side-chain.
These compounds are antagonists of the integrin receptor xcex1vxcex23 and are therefore useful for inhibiting bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammatory arthritis, cancer, and metastatic tumor growth. They are particularly useful for inhibiting bone resorption and for the treatment and prevention of osteoporosis.
Processes for the preparation of the enantiomerically enriched (R) and (S) forms of the above compound are disclosed in U.S. Pat. No. 6,017,926 and WO 01/34602. A key intermediate in these published processes is enantiomerically enriched 3(S)- or 3(R)-(6-methoxy-pyridin-3-yl)-xcex2-alanine methyl, ethyl or tert-butyl ester of structural formulae (1) and (2), respectively. 
The published chemical routes to the above chiral xcex2-amino acids involve a diastereoselective Michael addition of the lithium amide derived from N-benzyl-(S)- or (R)-2-methylbenzylamine using conditions described by Davies et al., in Tetrahedron: Asymmetry, Vol. 2, pp. 183-186, 1991. However, this methodology suffers from economic disadvantages associated with the high costs of reagents in the Davies chemistry and from operational limitations in the diastereoselective Michael addition reaction. The present invention is concerned with a short and efficient route to enantiomerically enriched mixtures of alkyl esters of 3-(6-methoxy-pyridin-3-yl)-xcex2-alanine which employs a chiral resolution by crystallization.
The present invention encompasses a process for the preparation of enantiomerically enriched mixtures of alkyl esters of 3-(6-methoxy-pyridin-3-yl)-xcex2-alanine which are useful in the synthesis of integrin xcex1vxcex23 antagonists. Another aspect of the present invention is concerned with novel salts of 3-(6-methoxy-pyridin-3-yl)-xcex2-alanine alkyl esters and a enantiomerically enriched N-protected-xcex1-amino acid.
One aspect of the present invention is concerned with a process for the preparation of enantiomerically enriched mixtures of compounds of structural I: 
wherein
R1 is C1-4 alkyl;
comprising the steps of:
(a) mixing a compound of structural formula I with an (R)- or (S)-amino acid of structural formula II: 
xe2x80x83wherein R2 is selected from the group consisting of phenyl, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, 4-imidazolylmethyl, and 4-hydroxybenzyl; and and R3 is tert-butyl, benzyl or 9-fluorenylmethyl; in an alcohol solvent system;
(b) heating the mixture from about 10xc2x0 C. to about 100xc2x0 C.;
(c) allowing the mixture to cool so that a crystalline (R)- or (S)-amino acid salt of said compound of formula I is formed;
(d) filtering the mixture to separate the crystalline salt from the supernatant; and
(e) liberating said compound of formula I from the crystalline salt by treating the salt with a base.
In one embodiment of this aspect of the present invention, R1 is methyl, ethyl, or tert-butyl. In a second embodiment, R2 is benzyl. In a third embodiment, R3 is benzyl. In a class of the first embodiment, both R2 and R3 represent benzyl.
In a further embodiment, the amino acid used in Step (a) is N-(benzyloxycarbonyl)-(S)-phenylalanine.
In yet a further embodiment the alcohol solvent system is about 0% to about 50% water in an alcohol selected from the group consisting of methanol, ethanol, and isopropanol. In a class of this embodiment the alcohol solvent system is aquous ethanol or aqueous methanol.
The racemic amino ester for the chiral resolution step can be prepared as described in Scheme 1.
A partially enantiomerically enriched amino ester for further chiral resolution can be prepared as described in Scheme 2. This route is based on a published method for methyl 3-amino-3-(3-pyridyl)-propanoate [H. M. Zhong, et al., Tetrahedron Lett., 40: 7721-7725 (1999)]. 
Another aspect of the process of the present invention is concerned with a crystalline salt of the structural formula: 
wherein
R1 is C1-4 alkyl;
or the corresponding enantiomeric salt.
In one embodiment of this aspect, R1 is methyl.
The term xe2x80x9cenantiomerically enrichedxe2x80x9d is intended to include compounds that are enantiomerically pure.
The term xe2x80x9c% enantiomeric excessxe2x80x9d (abbreviated xe2x80x9ceexe2x80x9d) shall mean the % major enantiomer less the % minor enantiomer. Thus, an 80% enantiomeric excess corresponds to formation of 90% of one enantiomer and 10% of the other. The term xe2x80x9cenantiomeric excessxe2x80x9d is synonymous with the term xe2x80x9coptical purity.xe2x80x9d
The term xe2x80x9cCbzxe2x80x9d represents xe2x80x9cbenzyloxycarbonyl.xe2x80x9d
Representative experimental procedures utilizing the novel process of the present invention are detailed below. For purposes of illustration, the following Examples are directed to the preparation of enantiomerically enriched mixtures of 3(S)-(6-methoxy-pyridin-3-yl)-xcex2-alanine methyl ester, but doing so is not intended to limit the present invention to a process for making those specific mixtures.
The differential scanning calorimeter (DSC) curve was taken on a TA 2910 Differential Scanning Calorimeter with a heating rate of 10xc2x0 C./minute under nitrogen.
X-ray powder diffraction patterns were generated on a Philip Analytical X-ray diffractometer using Cu Kxcex1 radiation. The experiments were run at ambient condition.